Heart failure currently affects over 5 million people in the United States. In a large subset of patients, heart failure is due to insufficient cardiac adaptation to hemodynamic stresses such as pressure or volume overload. Therefore, improving cardiac stress adaptation would benefit many heart failure patients. While several signaling pathways important for cardiac stress adaptation have been defined, it is not known whether signaling through such pathways is governed by upstream master regulators. A candidate master regulator of cardiac stress adaptation is the protein tyrosine phosphatase SHP2. SHP2 is indispensable in the developing heart, but whether SHP2 actively supports cardiac homeostasis throughout life is not known. Therefore, our objective is to define SHP2's function as a signal regulator in the context of cardiac stress adaptation. Our rationale is that deeper insight into the cardiac stress response will facilitate the design of novel therapeutic approaches aimed at SHP2 or SHP2-dependent signaling. We propose that SHP2 plays a critical role in cardiac stress adaptation based on three key preliminary findings that relate to each of the Specific Aims below: (1) SHP2's catalytic activity is increased in normal hearts under stress. (2) If SHP2's activity is impaired, transgenic mouse hearts fail to adapt normally to cardiovascular challenge. (3) Loss of SHP2 activity causes Akt hyperactivation, and reduction of Akt protein counteracts the detrimental effects of inactive SHP2. Our data suggest that SHP2's normal role is to act as a brake by preventing excessive and therefore detrimental Akt activation, while allowing sufficient increases in Akt activation to appropriately respond to stres. Therefore, our central hypothesis is that SHP2 has a beneficial role as an essential regulator of cardiac stress adaptation by limiting maximal Akt activation. To test this, we will measure the extent of SHP2 activation in normal mouse hearts and assess when and how SHP2's enzymatic activity changes under cardiac stress (Aim 1). Using transgenic approaches, we will determine the necessity of SHP2 activity for adaptation to physiologic and pathologic forms of cardiovascular stress and whether SHP2 prevents excessive Akt activation (Aim 2). We will also establish that tight control of the level of Akt activation is a critical function of SHP2 by crossng mice with inactive SHP2 with mice lacking Akt (Aim 3). Taken together, data from these three Aims will provide essential new insight into cardiac stress adaptation and define a novel role for SHP2 in the heart. The proposed studies will facilitate the design of novel therapeutic approaches aimed at improving the heart's ability to adapt to cardiovascular challenges.